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Fructose diet ameliorate effects of macrophage migration inhibitory factor deficiency on prefrontal cortex
Miloš Vratarić1, Vladimir Šenk1, Biljana Bursać1
1Department of Biochemistry, Institute for Biological Research "Siniša Stanković"- National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia.
Abstract:
Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that represents a link between diet-induced inflammation and insulin resistance. Our aim was to examine whether fructose diet affects inflammation and insulin signaling in the prefrontal cortex (PFC) of Mif knockout mice (MIF-KO), and their possible link to neural plasticity and behavior. We analyzed nuclear factor κB (NF-κB) and glucocorticoid signaling, expression of F4/80, IL-1β, TNF-α, TLR-4, MyD88, arginase 1 (Arg-1), mannose receptor (Mrc-1), and leukemia inhibitory factor (Lif) to assess inflammation in the PFC of C57/BL6J and MIF-KO mice consuming 20% fructose solution for 9 weeks. Insulin receptor (IR), IRS-1 serine phosphorylations (307 and 1101) and activity of PKCα, Akt, GSK-3β and AMPKα were used to analyze insulin signaling. Brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) mRNA levels, together with synapthophysin and PSD-95 protein level and calcium calmodulin-dependent kinase 2 (CaMKII) activity, were used as plasticity markers. Behavior was examined in elevated plus maze, light dark box and novel object recognition test. The results showed concomitant increase of Tnf-α, Tlr-4, MyD88 and M2 microglia markers (Arg-1, Mrc-1, Lif) in the PFC of MIF-KO, paralleled with unchanged glucocorticoid and insulin signaling. Increase of BDNF and IGF-1 was paralleled with increased CaMKII activity, decreased PSD-95 protein level, anxiogenic behavior, and impaired memory in MIF-KO mice. Fructose feeding restored these parameters in the PFC to the control level and mitigated behavioral changes, suggesting that ameliorating effects of fructose on neuroinflammation and behavior depend on the presence of MIF.
Insights
Macrophage migration inhibitory factor (MIF) absence exacerbates neuroinflammation and impairs cognitive function in mice. Fructose consumption mitigated these effects, highlighting MIF
Area of Science:
- Neuroscience
- Immunology
- Metabolic Disorders
Background:
- Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine linking diet-induced inflammation and insulin resistance.
- The prefrontal cortex (PFC) is crucial for cognitive functions and is susceptible to inflammatory insults.
Purpose of the Study:
- To investigate the impact of fructose diet on inflammation, insulin signaling, neural plasticity, and behavior in MIF knockout (MIF-KO) mice.
- To determine the role of MIF in mediating fructose's effects on the PFC.
Main Methods:
- Mice (C57/BL6J and MIF-KO) were fed a 20% fructose solution for 9 weeks.
- Inflammation, insulin signaling, neural plasticity markers, and behavioral tests were analyzed in the PFC.
- Key markers included NF-κB, glucocorticoid signaling, cytokines (TNF-α, IL-1β), microglial markers (F4/80, Arg-1, Mrc-1, Lif), insulin signaling proteins, neurotrophic factors (BDNF, IGF-1), and synaptic proteins (synaptophysin, PSD-95).
Main Results:
- MIF-KO mice exhibited increased neuroinflammation (TNF-α, TLR-4, MyD88) and M2 microglia markers (Arg-1, Mrc-1, Lif) in the PFC.
- Insulin signaling remained unchanged, but neural plasticity markers (BDNF, IGF-1) increased, accompanied by elevated CaMKII activity, reduced PSD-95, anxiety, and memory deficits.
- Fructose feeding normalized these parameters in MIF-KO mice and improved behavior, indicating MIF's protective role.
Conclusions:
- MIF deficiency exacerbates fructose-induced neuroinflammation and cognitive impairments in the PFC.
- Fructose's beneficial effects on neuroinflammation and behavior are dependent on the presence of MIF.
- These findings underscore MIF's critical role in regulating brain responses to dietary challenges.
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